Synthesis of medium and large phostams, phostones, and phostines

Phostams, phostones, and phostines are a series of 1,2-azaphosphaheterocycle and 1,2-oxaphosphaheterocycle 2-oxide derivatives. They are phosphorus analogues of lactams and lactones and important biologically active compounds. The strategies for the synthesis of medium and large phostams, phostones, and phostines are summarized. They include cyclizations and annulations. Cyclizations achieve ring construction through the formations of C–C, C–O, P–C, and P–O bonds in the rings, while annulations build the rings via [5 + 2], [6 + 1], and [7 + 1] fashions with the stepwise formation of two ring bonds. This review includes the recent syntheses of seven to fourteen-membered phostam, phostone, and phostine derivatives.

Cyclizations and annulations are two major strategies for the synthesis of medium and large phostam, phostone, and phostine derivatives. The cyclizations have been applied in the construction of C-C, C-O, P-C, and P-O bonds in the rings, while annulations are composed of  [5 + 2], [6 + 1], and [7 + 1] fashions for the formation of the rings (Figure 2). This review includes the synthesis of seven to fourteen-membered phostam, phostone, and phostine derivatives. Aboundant methods have been developed for the synthesis of seven-membered phostone and phostine derivatives.

Review 1 Synthesis via cyclizations
Cyclizations are major strategies for the construction of medium and large phostams, phostones, and phostines via C-C, C-O, P-C, and P-O bond formations, respectively. These strategies can be applied for the synthesis of seven to fourteenmembered phostam, phostone, and phostine derivatives.

Synthesis via C-C bond formation
Most medium and large phostams, phostones, and phostines were prepared via C-C bond formation, especially via ringclosing metathesis (RCM).

Synthesis via C-C bond formation through RCM reaction:
Ring-closing metathesis (RCM) is an efficient strategy for the construction of common to large cyclic compounds via the formation of a C=C bond [26], which can be further reduced to a C-C bond.

Synthesis via annulations
Annulations are alternative strategies for the synthesis of medium and large phostam, phostone, and phostine derivatives through a stepwise bond formation fashion. To date, [5 + 2], [6 + 1], and [7 + 1] annulations have been developed for the synthesis of medium phostams and phostones.
When Fuchs and co-workers investigated the conversion of cyclic vinyl sulfones to vinylphosphonates, they found that the reaction of (1S,2R)-2-methyl-3-(phenylsulfonyl)cyclohept-3-en-1-ol (100) and diethyl phosphonate generated (1R,5S,7S,8S,9R)-7-ethoxy-9-methyl-8-(phenylsulfonyl)-6-oxa-7-phosphabicyclo[3.2.2]nonane 7-oxide (101) in 87% yield in the presence of NaHMDS via Michael addition and intramolecular transesterification. The product is a bicycic 1,2-oxaphosphepane 2-oxide derivative (Scheme 21) [43].  construction of the rings. However, the synthetic methods are still limited, especially for asymmetric synthetic methods. Thus, it is clear that highly stereoselective asymmetric synthetic methods to access various medium and large phostam, phostone, and phostine derivatives are in high demand and should be developed in the near future for potential biological investigations. On the other hand, various methods have been developed for the synthesis of medium and large phostones and phostines, while only limited strategies have been achieved for the preparation of seven-and eight-membered phostams possibly because the P-O bond is more stable than the corresponding P-N bond. Much attention should be paid to the synthesis of different ring size phostams in the future.